Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase known to play a role in regulating cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription. Dysregulation of the mTOR pathway is implicated as a contributing factor to various human diseases, particularly various types of cancer. Rapamycin is a natural product produced by the bacterium Streptomyces hygroscopicus that can inhibit mTOR through association with its intracellular receptor FK-506 binding protein 12 (FKBP12). The FKBP12-rapamycin complex binds directly to the FKBP12-rapamycin binding domain of mTOR.
It has been demonstrated that mTOR functions as a catalytic subunit for two distinct molecular complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In addition to mTOR, mTORC1 is composed of regulatory associated protein of mTOR (Raptor) and mammalian LST8/G-protein β-subunit like protein (mLST8/GβL). This complex functions as a nutrient/energy/redox sensor and plays a role in regulating protein synthesis. The activity of mTORC1 is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine) and oxidative stress (Hay and Sonenberg, Genes Dev. 18(16):1926-1945, 2004; Wullschleger et al., Cell 124(3):471-484). In contrast, mTORC1 is known to be inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid and curcumin (Beevers et al., Int. J. Cancer 119(4):757-764, 2006; McMahon et al., Mol. Endocrinol. 19(1):175-183). The components of mTORC2 are rapamycin-insensitive companion of mTOR (Rictor), GβL, mammalian stress-activated protein kinase interacting protein 1 and mTOR. mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42 and protein kinase C alpha (Sarbassov et al., Curr. Biol. 14(14): 1296-302, 2004; Sarbassov et al., Science 307(5712): 1098-101, 2005). Unlike mTORC1, mTORC2 is not sensitive to rapamycin.
A number of mTOR inhibitors are currently being used, or are currently being investigated in clinical trials, to treat a variety of conditions Inhibitors of mTOR, such as rapamycin, are known to exhibit immunosuppressive and anti-proliferative properties. Accordingly, mTOR inhibitors are routinely administered to transplant recipients to prevent organ or bone marrow rejection.
Vaccines are widely used to treat or prevent disease, including infectious disease and cancer. In order for a vaccine to be effective, sufficient immunological memory against the target pathogen or cancer must be elicited, which often requires more than one dose of vaccine. The ability to induce adequate immunological memory in a subject by administration of a single vaccine dose is desirable to achieve rapid vaccination, as well as to reduce cost and improve compliance. Thus, a need remains for methods of enhancing immune responses against candidate vaccines.